COMMENTARIES

Sleep-disordered Breathing: a Risk Factor of the Metabolic Syndrome in obese Children and Adolescents?

Stijn Verhulst, M.D., M.Sc.1, Luc Van Gaal, M.D., Ph.D. 2, Wilfried De Backer, M.D., Ph.D. 2, and Kristine Desager, M.D., Ph.D.1
1Dept. of Pediatrics, 2Diabetology, Metabolism and Clinical Nutrition, 3Respiratory Medicine
Antwerp University Hospital
Belgium
Please address correspondence to:
Dr. Stijn Verhulst
University of Antwerp - Campus Drie Eiken
Universiteitsplein 1
2610 Wilrijk, Belgium
E-mail: stijn.verhulst@ua.ac.be

Stijn Verhulst

The Metabolic Syndrome and Childhood Obesity

The metabolic syndrome is comprised of the clustering of the following cardiovascular risk factors: (central) obesity, insulin resistance, dyslipidemia, and hypertension. Most definitions in pediatric literature are derived of three definitions used in adults: WHO criteria, National Cholesterol Education Program’s Adult Treatment Panel III criteria, and International Diabetes Federation definition. These definitions are then modified to be used in children and adolescents, i.e. with age- and gender-specific criteria. The metabolic syndrome is also frequently accompanied by certain conditions which are not incorporated into the definition, i.e. hypercoagulability, fatty liver disease, and micro-albuminuria [1].

          In the pediatric population, the overall prevalence of the metabolic syndrome is estimated at 4%, but it is 20% to 50% in overweight children [1-3]. Furthermore, the metabolic syndrome during childhood and/or adolescence is already associated with cardiovascular morbidity in early adulthood [4-6].

          The pathophysiology of the metabolic syndrome is likely to be multifactorial. Genetic and environmental factors both play a role in the development of (central) obesity and insulin resistance. Insulin resistance is the core factor in the development of the metabolic syndrome and its associated abnormalities by its influence on numerous markers and effectors of cardiovascular disease [7].

Sleep-Disordered Breathing and Childhood Obesity

The most well-known component of the various sleep-disordered breathing entities is the obstructive sleep apnea syndrome (OSAS), which is characterized by recurrent events of partial and/or complete upper airway obstruction resulting in a disruption of normal ventilation and sleep [8]. Obstructive sleep-disordered breathing is also considered to be an entire continuum, which also encompasses the upper airway resistance syndrome, in which the increased resistance at the upper airway is sufficiently large to cause sleep fragmentation in the absence of blunt apneas and abnormalities in gas exchange; and primary or habitual snoring, which is considered to be a relatively more benign expression of abnormal upper airway resistance [9]. Overweight children and adolescents have a higher prevalence of habitual snoring and obstructive sleep apnea syndrome than normal-weight children, a risk modulated by both adenotonsillar hypertrophy and increasing body mass index [10]. On the other hand, there is no significant relationship between body fat distribution and obstructive sleep apnea in children [11]. Furthermore, obese children also express a high prevalence of serious desaturations preceded by central apneas [11]. Although central apneas – apneas without respiratory effort and without movements of thorax and abdomen – are a normal phenomenon in children, desaturations below 89% following central apnea are considered to be pathological [12]. The consequences of sleep-disordered breathing include intermittent hypoxia and desaturation, hypercapnia, and arousal from sleep. The main clinical consequences of sleep-disordered breathing are behavioral and neurocognitive complications [13]. Secondly, recent studies also show an effect of sleep apnea on early alterations in the metabolic and cardiovascular system, which will be discussed next. It is therefore important to be alert for the presence of sleep-disordered breathing in this high-risk population and to subsequently seek appropriate management.

Sleep-Disordered Breathing and the Metabolic Syndrome

Recently, our group published the first study on the relationship between sleep-disordered breathing and the metabolic syndrome in a clinical sample of overweight and obese children [14]. All children were in good general health and children were not included when they had any chronic medical condition, any genetic, neuromuscular, or craniofacial syndromes, or were receiving medications that are known to affect glucose homeostasis or serum lipids. All subjects underwent anthropometry and overweight and obesity were defined according to the International Obesity Task Force criteria. A fasting blood measurement, an oral glucose tolerance test, and full nocturnal sleep studies were also performed. The metabolic syndrome was present if ≥ three of the following were positive: 1) waist circumference ≥ 90th percentile adjusted for age and sex; 2) fasting glucose ≥ 110 mg/dl; 3) fasting triglycerides ≥ 110 mg/dl; 4) fasting HDL-cholesterol ≤ 40 mg/dl; 5) blood pressure ≥ 90th percentile adjusted for age and sex (NCEP's ATP III adapted definition for adolescents) [2]. In this study, a total of 104 subjects was included (44% boys, 58% prepubertal with a mean age of 11.1 ± 2.6 years, range: 6.1 – 16.7). Thirty-one per cent of the subjects were overweight and 69% were obese. All subjects were nondiabetic. The metabolic syndrome was present in 37% of our subjects. Two markers of the severity of sleep-disordered breathing were independent predictors of the metabolic syndrome, namely the mean saturation during sleep (odds ratio = 0.54; 95% confidence interval = 0.30-0.97) and the maximal desaturation during sleep (odds ratio = 0.89; 95% confidence interval = 0.79-0.99), while controlling for gender, puberty, and body mass index. Furthermore, our study also showed multiple independent correlations between the severity of sleep apnea and glucose levels during the oral glucose tolerance test, and fasting triglycerides, cholesterol, and HDL-cholesterol. Only one other study investigated the association between sleep apnea and the metabolic syndrome in overweight adolescents and found similar results [15]. Other studies in overweight children have also found associations between sleep disordered breathing and insulin resistance [16,17] and between sleep apnea and hypertension [18,19].

          Other manifestations of the metabolic syndrome include non-alcoholic fatty liver disease and mico-albuminuria. Sleep-disordered breathing could be implicated in the development of both these associations. Preliminary, unpublished data from our group provides further evidence for this hypothesis. Recently, Krishna et al. found some evidence for early kidney dysfunction in a mixed sample of normal-weight and overweight children with sleep apnea [20].

          In summary, by aggravating the obesity-related hyperinsulinemia, dyslipidemia, and/or hypertension, sleep-disordered breathing could be an additional risk factor for developing the metabolic syndrome and cardiovascular disease in later life. Mechanisms by which sleep-disordered breathing may disturb metabolic control include increased sympathetic activity [21], higher serum cortisol [22], the formation of reactive oxygen species [23], and oxidative stress [24] resulting in increased inflammation [25] and impaired glucose tolerance and appetite regulation resulting from secondary sleep debt [26]. Longitudinal and interventional studies are urgently warranted to further examine the influence of sleep-disordered breathing on the development of cardiovascular morbidity in this high-risk population. In view of the high prevalence of sleep apnea in obese children and adolescents and of the influence of sleep apnea on metabolic control, obese children should be screened for the presence of sleep-disordered breathing and should be adequately treated as a mean of preventing cardiovascular disease in early adulthood.

References

  1.    Invitti C, Maffeis C, Gilardini L, et al. Metabolic syndrome in obese Caucasian children: prevalence using WHO-derived criteria and association with nontraditional cardiovascular risk factors. Int J Obes (Lond) 2006 Apr;30(4):627-33.
  2.    Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med 2003 Aug;157(8):821-27.
  3.    Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004 Jun 3;350(23):2362-74.
  4.    Berenson GS, Srinivasan SR, Bao W, Newman WP, III, Tracy RE, Wattigney WA. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998 Jun 4;338(23):1650-56.
  5.    Steinberger J, Moran A, Hong CP, Jacobs DR, Jr., Sinaiko AR. Adiposity in childhood predicts obesity and insulin resistance in young adulthood. J Pediatr 2001 Apr;138(4):469-73.
  6.    Sinaiko AR, Steinberger J, Moran A, Hong CP, Prineas RJ, Jacobs DR, Jr. Influence of insulin resistance and body mass index at age 13 on systolic blood pressure, triglycerides, and high-density lipoprotein cholesterol at age 19. Hypertension 2006 Oct;48(4):730-36.
  7.    Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature 2006 Dec 14;444(7121):875-80.
  8.    Standards and indications for cardiopulmonary sleep studies in children. American Thoracic Society. Am J Respir Crit Care Med 1996 Feb;153(2):866-78.
  9.    Greene MG, Carroll JL. Consequences of sleep-disordered breathing in childhood. Curr Opin Pulm Med 1997 Nov;3(6):456-63.
  10.    Tauman R, Gozal D. Obesity and obstructive sleep apnea in children. Paediatr Respir Rev 2006 Dec;7(4):247-59.
  11.    Verhulst SL, Schrauwen N, Haentjens D, et al. Sleep-disordered breathing in overweight and obese children and adolescents: prevalence, characteristics and the role of fat distribution. Arch Dis Child 2007 Mar;92(3):205-8.
  12.    Verhulst SL, Schrauwen N, Haentjens D, Van Gaal L, De Backer WA, Desager KN. Reference values for sleep-related respiratory variables in asymptomatic European children and adolescents. Pediatr Pulmonol 2007 Feb;42(2):159-67.
  13.    Beebe DW. Neurobehavioral morbidity associated with disordered breathing during sleep in children: a comprehensive review. Sleep 2006 Sep 1;29(9):1115-34.
  14.    Verhulst SL, Schrauwen N, Haentjens D, et al. Sleep-disordered breathing and the metabolic syndrome in overweight and obese children and adolescents. J Pediatr 2007;150(6):612-16.
  15.    Redline S, Storfer-Isser A, Rosen CL, et al. Association between metabolic syndrome and sleep disordered breathing in adolescents. Am J Respir Crit Care Med 2007 May 31.
  16.    de la Eva RC, Baur LA, Donaghue KC, Waters KA. Metabolic correlates with obstructive sleep apnea in obese subjects. J Pediatr 2002 Jun;140(6):654-59.
  17.    Li AM, Chan MH, Chan DF, et al. Insulin and obstructive sleep apnea in obese Chinese children. Pediatr Pulmonol 2006 Dec;41(12):1175-81.
  18.    Reade EP, Whaley C, Lin JJ, McKenney DW, Lee D, Perkin R. Hypopnea in pediatric patients with obesity hypertension. Pediatr Nephrol 2004 Sep;19(9):1014-20.
  19.    Leung LC, Ng DK, Lau MW, et al. Twenty-four-hour ambulatory BP in snoring children with obstructive sleep apnea syndrome. Chest 2006 Oct;130(4):1009-17.
  20.    Krishna J, Shah ZA, Merchant M, Klein JB, Gozal D. Urinary protein expression patterns in children with sleep-disordered breathing: preliminary findings. Sleep Med 2006 Apr;7(3):221-27.
  21.    Aljadeff G, Gozal D, Schechtman VL, Burrell B, Harper RM, Ward SL. Heart rate variability in children with obstructive sleep apnea. Sleep 1997 Feb;20(2):151-57.
  22.    Bratel T, Wennlund A, Carlstrom K. Pituitary reactivity, androgens and catecholamines in obstructive sleep apnoea. Effects of continuous positive airway pressure treatment (CPAP). Respir Med 1999 Jan;93(1):1-7.
  23.    Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 2002 Apr 1;165(7):934-39.
  24.    Verhulst SL, Van HK, Schrauwen N, et al. Sleep-disordered breathing and uric acid in overweight and obese children and adolescents. Chest 2007 Jul;132(1):76-80.
  25.    Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000 Apr;85(3):1151-58.
  26.    Spiegel K, Knutson K, Leproult R, Tasali E, Van CE. Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J Appl Physiol 2005 Nov;99(5):2008-19.

 

 

CLOSE THE WINDOW